| Structural highlights
4ehh is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | NonStd Res: | , |
| Related: | 4eha, 4ehd, 4ehf, 4ehk, 4ehl, 4ehn |
| Gene: | CASP3, CPP32 (HUMAN) |
| Activity: | Caspase-3, with EC number 3.4.22.56 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[CASP3_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage.[1] [2]
Publication Abstract from PubMed
A mutation in the allosteric site of the caspase-3 dimer interface of V266 to histidine abolishes activity of the enzyme, and models predict that the mutation mimics the action of small molecule allosteric inhibitors by preventing formation of the active site. Mutations were coupled to H266 at two sites in the interface, E124A and Y197C. We present data from X-ray crystallography, enzymatic activity and molecular dynamics simulations for seven proteins, consisting of single, double, and triple mutants. The data demonstrate that considering allosteric inhibition of caspase-3 as a shift between discrete "off-state" or "on-state" conformations is insufficient. While H266 is accommodated in the interface, the structural defects are propagated to the active site through a helix on the protein surface. A more comprehensive view of allosteric regulation of caspase-3 requires the representation of an ensemble of inactive states and shows that subtle structural changes lead to the population of the inactive ensemble.
Allosteric Modulation of Caspase-3 through Mutagenesis.,Walters J, Schipper JL, Swartz P, Mattos C, Clark AC Biosci Rep. 2012 May 18. PMID:22607239[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al.. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995 Jul 6;376(6535):37-43. PMID:7596430 doi:http://dx.doi.org/10.1038/376037a0
- ↑ Cabrera JR, Bouzas-Rodriguez J, Tauszig-Delamasure S, Mehlen P. RET modulates cell adhesion via its cleavage by caspase in sympathetic neurons. J Biol Chem. 2011 Apr 22;286(16):14628-38. doi: 10.1074/jbc.M110.195461. Epub, 2011 Feb 28. PMID:21357690 doi:10.1074/jbc.M110.195461
- ↑ Walters J, Schipper JL, Swartz P, Mattos C, Clark AC. Allosteric Modulation of Caspase-3 through Mutagenesis. Biosci Rep. 2012 May 18. PMID:22607239 doi:10.1042/BSR20120037
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